Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK)

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Abstract

A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar Ki’s against SYK and potent inhibition in mast cell degranulation assays.

Graphical abstract

The synthesis of potent novel SYK inhibitors such as 17 (Ki = 8 nm) is reported.

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Cited by (32)

  • In silico structural anatomization of spleen tyrosine kinase inhibitors: Pharmacophore modeling, 3D QSAR analysis and molecular docking studies

    2019, Journal of Molecular Structure
    Citation Excerpt :

    Thus, out of all the molecular scaffolds, imidazopyrazine based molecules, i.e., A, C and D series have positive interactions and show good biological activity. To gain more insight on ligand and protein receptor interactions molecular docking was performed with a crystal structure of Syk 3EMG [29]. The docking results similar to 3D QSAR model showed that the important interactions are H-bonding, hydrophobic and electrostatic as presented in Table S3.

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Present address: Novartis, Cambridge, MA, USA.

Present address: Wyeth Reserch, Collegeville, PA, USA.

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